Dose-limiting toxicity after hypofractionated dose-escalated radiotherapy in non-small-cell lung cancer

Donald M. Cannon, Minesh P. Mehta, Jarrod B. Adkison, Deepak Khuntia, Anne M. Traynor, Wolfgang A. Tome, Richard J. Chappell, Ranjini Tolakanahalli, Pranshu Mohindra, Søren M. Bentzen, George M. Cannon

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Abstract

Purpose Local failure rates after radiation therapy (RT) for locally advanced non-small-cell lung cancer (NSCLC) remain high. Consequently, RT dose intensification strategies continue to be explored, including hypofractionation, which allows for RT acceleration that could potentially improve outcomes. The maximum-tolerated dose (MTD) with dose-escalated hypofractionation has not been adequately defined. Patients and Methods Seventy-nine patients with NSCLC were enrolled on a prospective single-institution phase I trial of dose-escalated hypofractionated RT without concurrent chemotherapy. Escalation of dose per fraction was performed according to patients' stratified risk for radiation pneumonitis with total RT doses ranging from 57 to 85.5 Gy in 25 daily fractions over 5 weeks using intensity-modulated radiotherapy. The MTD was defined as the maximum dose with ≤ 20% risk of severe toxicity. Results No grade 3 pneumonitis was observed and an MTD for acute toxicity was not identified during patient accrual. However, with a longer follow-up period, grade 4 to 5 toxicity occurred in six patients and was correlated with total dose (P = .004). An MTD was identified at 63.25 Gy in 25 fractions. Late grade 4 to 5 toxicities were attributable to damage to central and perihilar structures and correlated with dose to the proximal bronchial tree. Conclusion Although this dose-escalation model limited the rates of clinically significant pneumonitis, dose-limiting toxicity occurred and was dominated by late radiation toxicity involving central and perihilar structures. The identified dose-response for damage to the proximal bronchial tree warrants caution in future dose-intensification protocols, especially when using hypofractionation.

Original languageEnglish (US)
Pages (from-to)4343-4348
Number of pages6
JournalJournal of Clinical Oncology
Volume31
Issue number34
DOIs
StatePublished - Dec 1 2013

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Non-Small Cell Lung Carcinoma
Maximum Tolerated Dose
Radiotherapy
Pneumonia
Radiation Pneumonitis
Intensity-Modulated Radiotherapy
Dose Hypofractionation
Radiation
Drug Therapy

ASJC Scopus subject areas

  • Cancer Research
  • Oncology
  • Medicine(all)

Cite this

Cannon, D. M., Mehta, M. P., Adkison, J. B., Khuntia, D., Traynor, A. M., Tome, W. A., ... Cannon, G. M. (2013). Dose-limiting toxicity after hypofractionated dose-escalated radiotherapy in non-small-cell lung cancer. Journal of Clinical Oncology, 31(34), 4343-4348. https://doi.org/10.1200/JCO.2013.51.5353

Dose-limiting toxicity after hypofractionated dose-escalated radiotherapy in non-small-cell lung cancer. / Cannon, Donald M.; Mehta, Minesh P.; Adkison, Jarrod B.; Khuntia, Deepak; Traynor, Anne M.; Tome, Wolfgang A.; Chappell, Richard J.; Tolakanahalli, Ranjini; Mohindra, Pranshu; Bentzen, Søren M.; Cannon, George M.

In: Journal of Clinical Oncology, Vol. 31, No. 34, 01.12.2013, p. 4343-4348.

Research output: Contribution to journalArticle

Cannon, DM, Mehta, MP, Adkison, JB, Khuntia, D, Traynor, AM, Tome, WA, Chappell, RJ, Tolakanahalli, R, Mohindra, P, Bentzen, SM & Cannon, GM 2013, 'Dose-limiting toxicity after hypofractionated dose-escalated radiotherapy in non-small-cell lung cancer', Journal of Clinical Oncology, vol. 31, no. 34, pp. 4343-4348. https://doi.org/10.1200/JCO.2013.51.5353
Cannon, Donald M. ; Mehta, Minesh P. ; Adkison, Jarrod B. ; Khuntia, Deepak ; Traynor, Anne M. ; Tome, Wolfgang A. ; Chappell, Richard J. ; Tolakanahalli, Ranjini ; Mohindra, Pranshu ; Bentzen, Søren M. ; Cannon, George M. / Dose-limiting toxicity after hypofractionated dose-escalated radiotherapy in non-small-cell lung cancer. In: Journal of Clinical Oncology. 2013 ; Vol. 31, No. 34. pp. 4343-4348.
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abstract = "Purpose Local failure rates after radiation therapy (RT) for locally advanced non-small-cell lung cancer (NSCLC) remain high. Consequently, RT dose intensification strategies continue to be explored, including hypofractionation, which allows for RT acceleration that could potentially improve outcomes. The maximum-tolerated dose (MTD) with dose-escalated hypofractionation has not been adequately defined. Patients and Methods Seventy-nine patients with NSCLC were enrolled on a prospective single-institution phase I trial of dose-escalated hypofractionated RT without concurrent chemotherapy. Escalation of dose per fraction was performed according to patients' stratified risk for radiation pneumonitis with total RT doses ranging from 57 to 85.5 Gy in 25 daily fractions over 5 weeks using intensity-modulated radiotherapy. The MTD was defined as the maximum dose with ≤ 20{\%} risk of severe toxicity. Results No grade 3 pneumonitis was observed and an MTD for acute toxicity was not identified during patient accrual. However, with a longer follow-up period, grade 4 to 5 toxicity occurred in six patients and was correlated with total dose (P = .004). An MTD was identified at 63.25 Gy in 25 fractions. Late grade 4 to 5 toxicities were attributable to damage to central and perihilar structures and correlated with dose to the proximal bronchial tree. Conclusion Although this dose-escalation model limited the rates of clinically significant pneumonitis, dose-limiting toxicity occurred and was dominated by late radiation toxicity involving central and perihilar structures. The identified dose-response for damage to the proximal bronchial tree warrants caution in future dose-intensification protocols, especially when using hypofractionation.",
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AU - Khuntia, Deepak

AU - Traynor, Anne M.

AU - Tome, Wolfgang A.

AU - Chappell, Richard J.

AU - Tolakanahalli, Ranjini

AU - Mohindra, Pranshu

AU - Bentzen, Søren M.

AU - Cannon, George M.

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N2 - Purpose Local failure rates after radiation therapy (RT) for locally advanced non-small-cell lung cancer (NSCLC) remain high. Consequently, RT dose intensification strategies continue to be explored, including hypofractionation, which allows for RT acceleration that could potentially improve outcomes. The maximum-tolerated dose (MTD) with dose-escalated hypofractionation has not been adequately defined. Patients and Methods Seventy-nine patients with NSCLC were enrolled on a prospective single-institution phase I trial of dose-escalated hypofractionated RT without concurrent chemotherapy. Escalation of dose per fraction was performed according to patients' stratified risk for radiation pneumonitis with total RT doses ranging from 57 to 85.5 Gy in 25 daily fractions over 5 weeks using intensity-modulated radiotherapy. The MTD was defined as the maximum dose with ≤ 20% risk of severe toxicity. Results No grade 3 pneumonitis was observed and an MTD for acute toxicity was not identified during patient accrual. However, with a longer follow-up period, grade 4 to 5 toxicity occurred in six patients and was correlated with total dose (P = .004). An MTD was identified at 63.25 Gy in 25 fractions. Late grade 4 to 5 toxicities were attributable to damage to central and perihilar structures and correlated with dose to the proximal bronchial tree. Conclusion Although this dose-escalation model limited the rates of clinically significant pneumonitis, dose-limiting toxicity occurred and was dominated by late radiation toxicity involving central and perihilar structures. The identified dose-response for damage to the proximal bronchial tree warrants caution in future dose-intensification protocols, especially when using hypofractionation.

AB - Purpose Local failure rates after radiation therapy (RT) for locally advanced non-small-cell lung cancer (NSCLC) remain high. Consequently, RT dose intensification strategies continue to be explored, including hypofractionation, which allows for RT acceleration that could potentially improve outcomes. The maximum-tolerated dose (MTD) with dose-escalated hypofractionation has not been adequately defined. Patients and Methods Seventy-nine patients with NSCLC were enrolled on a prospective single-institution phase I trial of dose-escalated hypofractionated RT without concurrent chemotherapy. Escalation of dose per fraction was performed according to patients' stratified risk for radiation pneumonitis with total RT doses ranging from 57 to 85.5 Gy in 25 daily fractions over 5 weeks using intensity-modulated radiotherapy. The MTD was defined as the maximum dose with ≤ 20% risk of severe toxicity. Results No grade 3 pneumonitis was observed and an MTD for acute toxicity was not identified during patient accrual. However, with a longer follow-up period, grade 4 to 5 toxicity occurred in six patients and was correlated with total dose (P = .004). An MTD was identified at 63.25 Gy in 25 fractions. Late grade 4 to 5 toxicities were attributable to damage to central and perihilar structures and correlated with dose to the proximal bronchial tree. Conclusion Although this dose-escalation model limited the rates of clinically significant pneumonitis, dose-limiting toxicity occurred and was dominated by late radiation toxicity involving central and perihilar structures. The identified dose-response for damage to the proximal bronchial tree warrants caution in future dose-intensification protocols, especially when using hypofractionation.

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